Previous studies on impaired fetal growth have identified multiple risk factors including environmental tobacco smoke (ETS), social stress, lead exposure and air pollution. In parallel, a growing body of literature has demonstrated that all 4 of these risk factors can alter DNA methylation, suggesting a common pathway by which such environmental factors impair fetal growth. The key to understanding the role of environment in impairing fetal growth is to 1) measure environmental risk factors prospectively in pregnancy, to ensure that exposure and subsequent epigenetic changes are temporally associated and 2) to measure epigenetic changes in the correct target tissues. While a case control design may be more efficient, such a design could not tease out whether methylation changes were due to environmental factors or were constitutive in impaired growth. This point is critical as reducing risk by intervening on environmental factors requires knowledge of their mechanisms. To this end, this proposal will utilize the existing infrastructure of the ELEMENT birth cohort study in Mexico and a second ongoing study of similar design in Boston-PRISM. ELEMENT and PRISM have archived umbilical cord vessels and placenta as well as ETS, stress, air pollution and lead exposure measured prospectively beginning in the early 2nd trimester and data on fetal growth. We are therefore uniquely positioned to address these important questions. In this proposal, we hypothesize that common environmental risk factors that impair fetal growth will alter methylomic marks in target tissues critical for fetal growth. Fetal growth depends on maternal transport of nutrients as well as the transport and excretion of toxicants and waste products. Logical target tissues for fetal growth would be tissues of the vascular system (vessels, blood and placenta). Perhaps the greatest strength of our proposal is that we can assess multiple "target tissues" and can compare and contrast 450,000 unique methylation sites across these tissues in the context of environmental exposures. This study will make substantial contributions to our understanding the role of environment in fetal growth. PUBLIC HEALTH RELEVANCE: This project will identify DNA methylation alterations in umbilical vessels, placenta and fetal blood that are induced by exposure to environmental tobacco smoke, social stress, lead and air pollution. By conducting analyses on multiple tissues relevant to fetal growth, it will contribute to establishing how different exposures and tissues contribute to fetal growth.